1. Field of the Invention
The present invention relates to a process for separation of 19-nor-.DELTA..sup.4 -androstene-3,17-dione. More particularly, the present invention relates to a process for effectively separating 19-nor-.DELTA..sup.4 -androstene-3,17-dione (hereinafter abbreviated as ESD) in high purity as the C.sub.3 -enamine from a mixture of steroids.
2. Description of Prior Art
ESD, whose structure is illustrated by formula (A) below, is important as a preparative intermediate for a corpus luteum hormone, 19-nor-ethisterone, whose structure is shown by the following formula (B). The latter is obtained by ethynylation of ESD, and is useful as a main component of oral contraceptive pills. ESD is obtained by hydrolysis of the C.sub.3 -enamine of ESD. ##SPC3##
The principal technique for production of ESD is by Birch's reduction of an alkyl or aralkyl ether of estrone acetal, shown below by formulas (I) and (II), respectively, followed by hydrolysis of the product. However, in the past, it has been difficult to control the conversion of Birch's reduction, and the number of species and the quantities of by-products formed in the reaction have been found to vary widely depending upon the nature of the conversion. That is, in the above reaction, double-bond isomers such as 19-nor-.DELTA..sup.1 -androstene-3,17-dione, 19-nor-.DELTA..sup.1,.sup.(10) -androstene-3,17-dione, 19-nor-.DELTA..sup.5 -androstene-3,17-dione and the like; or 19-nor-androstane-3,17-dione and the like, in which the carbon-carbon double bond is completely hydrogenated, are formed as by-products in the formation of ESD. Additionally, the alkyl or aralkyl ether of estrone is formed by acetal hydrolysis from the alkyl or aralkyl ether of estrone acetal.
When the conversion percentage of Birch's reduction is high, a slight drop in the selectivity of the formation of ESD occurs. When the degree of conversion, defined as 100%- the percentage of unreacted starting material, becomes higher than 98%, especially higher than 99.5%, the amount of the 19-nor-androstane-3,17-dione produced in the saturated form increases rapidly. In view of this, it is preferred that the conversion of Birch's reduction be maintained below 99.5%, more preferably below 98%. On the other hand, it is found that if the conversion of Birch's reduction is lowered as described above, the alkyl or aralkyl ether of estrone formed by hydrolysis of the starting material is produced along with ESD. In addition, the alkyl or aralkyl ether of estrone becomes ethynylated, producing a compound showing strong estrogenic hormone action. Therefore, it is necessary to remove the alkyl or aralkyl ether of estrone from ESD prior to said ethynylation reaction. Furthermore, from an economical viewpoint, this by-product must be recovered for reuse.
Attempts have been made to separate the desired ESD from the mixture of steroids. One such technique attempted is by column chromatography. However, it has been found that separation of ESD by such a process is almost impossible on an industrial scale since ESD and the above described by-products are very similar in their physical properties.
Another method attempted for separating ESD from a mixture containing the steroids obtained by Birch's reduction and hydrolysis is by recrystallization. However, pure ESD cannot be obtained by this process either. This is because the alkyl or aralkyl ether of estrone, which is always present in the mixture of steroids as a result of low conversion of Birch's reduction, required to avoid the formation of undesired saturated 19-nor-androstane-3,17-dione, as previously described, crystallizes far more readily than either the desired ESD or the other by-products. Consequently, the crystals of ESD invariably become contaminated by the alkyl or aralkyl ether of estrone.
Still another attempted process for obtaining ESD is based on the known process for separating .DELTA..sup.4 -3-ketosteroids from ketones, or nonketonic materials, which are soluble in organic solvents and inert to the enamine formation reaction. This process comprises forming the enamines from a mixture of steroids containing .DELTA..sup.4 -3-ketosteroids, converting the obtained enamine derivatives of .DELTA..sup.4 -3-ketosteroids to their hydrochlorides, hydrobromides or hydroiodides by respectively adding hydrogen chloride, hydrogen bromide of hydrogen iodide, and then taking advantage of the solubilities of the said hydrochlorides in organic solvents such as methanol and the like or the insolubilities of the same in organic solvents, such as benzene-ether (1:1) or the like, or the insolubilities of the hydrobromides or hydroiodides in organic solvents, such as methanol or the like. (See J. Am. Chem. Soc. 78 434 (1956)). However, the ESD counterpart of the above process is troublesome and cannot be applied on an industrial scale. The reason is that in Birch's reduction of an alkyl or an aralkyl ether of estrone acetal followed by hydrolysis the control of conversion is relatively difficult and the species and the quantities of by-products are liable to fluctuate as mentioned previously. Since the conditions for selectively separating enamine salts of .DELTA..sup.4 -3-ketosteroids vary to a large extend depending upon the number of species and the relative quantities of the steroids present, the separation procedure would necessarily have to be varied continuously depending upon the conversion percentage of Birch's reduction. Furthermore, the alkyl or aralkyl ether of estrone which is formed by hydrolysis of the alkyl or aralkyl ether of estrone acetal in the course of Birch's reduction and subsequent hydrolysis is only soluble in organic solvents with difficulty, while the other products of said reaction are readily soluble in organic solvents.
Therefore, in separating the hydrochloride of C.sub.3 -enamine of ESD by taking advantage of the insolubility of said hydrochloride in organic solvents, such as benzene-ether (1:1) or the like, the enamine salt is contaminated by an alkyl or an aralkyl ether of estrone. This can be avoided if the HCl is introduced after the difficultly soluble alkyl or aralkyl ether of estrone, is first completely dissolved. However, as shown in Comparative Example 1, when it is attempted to completely dissolve the alkyl or an aralkyl ether of estrone so as to avoid contamination, 1 g of the reaction product of Birch's reduction and hydrolysis containing about 13% of the alkyl ether of estrone (87% conversion of Birch's reduction) cannot be dissolved in 100 ml of benzene-ether (1:1). Hence, the separation process is not appropriate for industrial use, since a large excess of said solvent must be used to obtain the enamine salt in high purity.
Consequently, it would be desirable to have a process for separating pure ESD from the Birch's reduction and hydrolysis reaction mixture by a process suitable for industrial use.